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1.
J Thromb Haemost ; 13(9): 1597-605, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26118944

RESUMO

BACKGROUND: Randomized controlled trials (RCTs) on pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success. METHODS: The Kids-DOTT trial is a multicenter RCT investigating non-inferiority of a 6-week (shortened) versus 3-month (conventional) duration of anticoagulation in patients aged < 21 years with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded-endpoint, parallel-cohort RCT design. RESULTS: No eligibility violations or randomization errors occurred. Of the enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in prespecified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Interobserver agreement between local and blinded central determination of venous occlusion by imaging at 6 weeks after diagnosis was strong (k-statistic = 0.75; 95% confidence interval [CI] 0.48-1.0). The primary efficacy and safety event rates were 3.3% (95% CI 0.3-11.5%) and 1.4% (95% CI 0.03-7.4%). CONCLUSIONS: The P/F phase of the Kids-DOTT trial has demonstrated the validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention and endpoint rates to inform the fully powered RCT.


Assuntos
Anticoagulantes/uso terapêutico , Trombose Venosa/tratamento farmacológico , Adolescente , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Criança , Pré-Escolar , Colorado/epidemiologia , Diagnóstico por Imagem , Determinação de Ponto Final/métodos , Estudos de Viabilidade , Feminino , Florida/epidemiologia , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Lactente , Masculino , Variações Dependentes do Observador , Projetos Piloto , Garantia da Qualidade dos Cuidados de Saúde , Recidiva , Reprodutibilidade dos Testes , Projetos de Pesquisa , Método Simples-Cego , Fatores de Tempo , Trombose Venosa/diagnóstico , Adulto Jovem
2.
J Thromb Haemost ; 13(8): 1405-13, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26052866

RESUMO

BACKGROUND: Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa. OBJECTIVES: To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF). METHODS: In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability. RESULTS: A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity. CONCLUSIONS: In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered.


Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Azepinas/administração & dosagem , Benzamidas/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Acidente Vascular Cerebral/prevenção & controle , Varfarina/administração & dosagem , Administração Oral , Idoso , Anticoagulantes/efeitos adversos , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Azepinas/efeitos adversos , Benzamidas/efeitos adversos , Biomarcadores/sangue , Método Duplo-Cego , Regulação para Baixo , Esquema de Medicação , Inibidores do Fator Xa/efeitos adversos , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Fatores de Tempo , Resultado do Tratamento , Varfarina/efeitos adversos
3.
Int J Clin Pract ; 69(7): 743-56, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25854636

RESUMO

BACKGROUND: Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major risk factor for stroke. Rivaroxaban, an oral factor Xa inhibitor, is approved for the prevention of stroke in patients with non-valvular AF. In the pivotal phase III trial ROCKET AF, rivaroxaban demonstrated non-inferiority compared with warfarin for reducing the risk of stroke or systemic embolism (SE) in patients with AF (intention-to-treat analysis), without an increased risk of major bleeding. Superior efficacy vs. warfarin was achieved while patients were on study medication. Other direct oral factor Xa inhibitors have completed phase III clinical trials in this indication. Compared with warfarin, apixaban (in the ARISTOTLE trial) and edoxaban (in the ENGAGE-AF trial) were shown to be superior or non-inferior, respectively, for reduction in stroke or SE risk in patients with AF. Baseline stroke risk, as indicated by CHADS2 scores, was lower in patients in the ARISTOTLE and ENGAGE-AF trials than in ROCKET AF. OBJECTIVES: This review discusses the main findings from ROCKET AF, specifically examining recent subgroup analyses investigating rivaroxaban use across various patient types at high risk for adverse outcomes, including those with prior stroke or transient ischaemic attack, reduced renal function, prior myocardial infarction, peripheral artery disease, heart failure or patients aged ≥ 75 years and those resident in East Asia. CONCLUSIONS: These subgroup analyses demonstrate that the treatment effect for rivaroxaban vs. warfarin is broadly consistent across a wide range of patient groups, with respect to both efficacy and safety.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Vigilância da População , Rivaroxabana/administração & dosagem , Acidente Vascular Cerebral , Administração Oral , Fibrilação Atrial/complicações , Inibidores do Fator Xa/administração & dosagem , Humanos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle
4.
J Clin Pharmacol ; 54(8): 917-27, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24668660

RESUMO

Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n = 161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF.


Assuntos
Fibrilação Atrial/metabolismo , Inibidores do Fator Xa , Modelos Biológicos , Morfolinas , Tiofenos , Idoso , Idoso de 80 Anos ou mais , Coagulação Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Fator Xa/metabolismo , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/sangue , Morfolinas/farmacocinética , Tempo de Protrombina , Insuficiência Renal/metabolismo , Rivaroxabana , Tiofenos/administração & dosagem , Tiofenos/sangue , Tiofenos/farmacocinética
5.
J Thromb Haemost ; 11(8): 1443-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23773172

RESUMO

Antithrombotic trials in venous thromboembolism treatment and prevention, including those evaluating the new oral anticoagulants, have typically evaluated thromboembolism risk as an efficacy endpoint and bleeding risk as a separate safety endpoint. Findings often occur in opposition (i.e. decreased thromboembolism accompanied by increased bleeding, or vice-versa), leading to variable interpretation of the results, which may ultimately be judged as equivocal. In this paper, we offer an alternative to traditional designs based on the concept of a bivariate primary endpoint that accounts for simultaneous effects on antithrombotic efficacy and harm due to bleeding. We suggest a bivariate endpoint as a general approach to the assessment of 'net clinical benefit' in recently published trials and to the design of future trials. Lastly, we illustrate the bivariate endpoint design using two examples: a recently published superiority trial of rivaroxaban (RECORD1) and an ongoing non-inferiority trial of the duration of anticoagulant therapy in children with venous thrombosis (Kids-DOTT).


Assuntos
Tromboembolia Venosa/terapia , Administração Oral , Anticoagulantes/uso terapêutico , Hemorragia/prevenção & controle , Humanos , Morfolinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Risco , Rivaroxabana , Tiofenos/uso terapêutico
7.
J Thromb Haemost ; 8(5): 1018-26, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20128861

RESUMO

SUMMARY BACKGROUND: Gene-based warfarin dosing algorithms have largely been developed in homogeneous populations, and their generalizability has not been established. OBJECTIVES: We sought to assess the performance of published algorithms in a racially diverse and multiethnic sample, and determine if additional clinical variables or genetic variants associated with dose could enhance algorithm performance. PATIENTS AND METHODS: In 145 compliant patients on warfarin with a goal international normalized ratio (INR) of 2-3, stable, therapeutic doses were compared with predicted doses using 12 reported algorithms that incorporated CYP2C9 and VKORC1 variants. Additional covariates tested with each model included race, concurrent medications, medications known to interact with warfarin and previously described CYP4F2, CALU and GGCX variants. RESULTS: The mean patient age was 67 +/- 14 years; 90 (62%) were male. Eighty-two (57%) were Caucasian, 28 (19%) African-American, 20 (14%) Hispanic and 15 (10%) Asian. The median warfarin dose was 35 mg per week (interquartile range 23-53 mg per week). Gene-based dosing algorithms explained 37-55% of the variation in warfarin dose requirements. Neither the addition of race, number of concurrent medications nor the number of concurrent medications interacting with warfarin enhanced algorithm performance. Similarly, consideration of CYP4F2, CALU or GGCX variant genotypes did not improve algorithms. CONCLUSIONS: Existing gene-based dosing algorithms explained between approximately one-third and one-half of the variability in warfarin dose requirements in this racially and ethnically diverse cohort. Additional clinical and recently described genetic variants associated with warfarin dose did not enhance prediction in our patient population.


Assuntos
Algoritmos , Anticoagulantes/administração & dosagem , Etnicidade/genética , Varfarina/administração & dosagem , Idoso , Relação Dose-Resposta a Droga , Feminino , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Farmacogenética
10.
Circulation ; 104(17): 2118-50, 2001 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-11673357
11.
J Am Coll Cardiol ; 38(4): 1231-66, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11583910
16.
N Engl J Med ; 344(19): 1411-20, 2001 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-11346805

RESUMO

BACKGROUND: The conventional treatment strategy for patients with atrial fibrillation who are to undergo electrical cardioversion is to prescribe warfarin for anticoagulation for three weeks before cardioversion. It has been proposed that if transesophageal echocardiography reveals no atrial thrombus, cardioversion may be performed safely after only a short period of anticoagulant therapy. METHODS: In a multicenter, randomized, prospective clinical trial, we enrolled 1222 patients with atrial fibrillation of more than two days' duration and assigned them to either treatment guided by the findings on transesophageal echocardiography or conventional treatment. The composite primary end point was cerebrovascular accident, transient ischemic attack, and peripheral embolism within eight weeks. Secondary end points were functional status, successful restoration and maintenance of sinus rhythm, hemorrhage, and death. RESULTS: There was no significant difference between the two treatment groups in the rate of embolic events (five embolic events among 619 patients in the transesophageal-echocardiography group [0.8 percent]) vs. three among 603 patients in the conventional-treatment group [0.5 percent], P=0.50). However, the rate of hemorrhagic events was significantly lower in the transesophageal-echocardiography group (18 events [2.9 percent] vs. 33 events [5.5 percent], P=0.03). Patients in the transesophageal-echocardiography group also had a shorter time to cardioversion (mean [+/-SD], 3.0+/-5.6 vs. 30.6+/-10.6 days, P<0.001) and a greater rate of successful restoration of sinus rhythm (440 patients [71.1 percent] vs. 393 patients [65.2 percent], P=0.03). At eight weeks, there were no significant differences between the two groups in the rates of death or maintenance of sinus rhythm or in functional status. CONCLUSIONS: The use of transesophageal echocardiography to guide the management of atrial fibrillation may be considered a clinically effective alternative strategy to conventional therapy for patients in whom elective cardioversion is planned.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/terapia , Ecocardiografia Transesofagiana , Cardioversão Elétrica , Cardiopatias/diagnóstico por imagem , Trombose/diagnóstico por imagem , Idoso , Anticoagulantes/efeitos adversos , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico por imagem , Cardioversão Elétrica/métodos , Embolia/etiologia , Feminino , Átrios do Coração/diagnóstico por imagem , Cardiopatias/tratamento farmacológico , Hemorragia/induzido quimicamente , Heparina/efeitos adversos , Heparina/uso terapêutico , Humanos , Ataque Isquêmico Transitório/etiologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Estudos Prospectivos , Acidente Vascular Cerebral/etiologia , Tromboembolia/prevenção & controle , Trombose/tratamento farmacológico , Varfarina/efeitos adversos , Varfarina/uso terapêutico
19.
Am J Med ; 109(1): 45-51, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10936477

RESUMO

PURPOSE: The risk of ischemic stroke varies widely among patients with nonvalvular atrial fibrillation, influencing the choice of prophylactic antithrombotic therapy. We assessed three schemes for stroke risk stratification in these patients who were treated with aspirin and who did not have prior cerebral ischemia. SUBJECTS AND METHODS: Criteria from three schemes of risk stratification were applied to a longitudinally observed cohort of patients with atrial fibrillation who did not have prior cerebral ischemia and who were treated with aspirin alone or aspirin combined with low, ineffective doses of warfarin in a multicenter clinical trial. The ability of the schemes to identify patients at high (>/=6%), low (75 years old as high risk (observed stroke rate 4.2 per 100 person-years), while the remaining scheme classified one third of patients in this age group as low risk (observed stroke rate 0.6 per 100 person-years). CONCLUSIONS: When tested in a large cohort of patients with atrial fibrillation who were treated with aspirin, available risk-stratification schemes successfully identified patients with low rates of ischemic stroke, but less consistently identified high-risk patients.


Assuntos
Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Fibrilação Atrial/complicações , Isquemia Encefálica/prevenção & controle , Inibidores da Agregação Plaquetária/uso terapêutico , Medição de Risco/métodos , Varfarina/uso terapêutico , Adulto , Fatores Etários , Idoso , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/etiologia , Quimioterapia Combinada , Seguimentos , Valvas Cardíacas , Humanos , Incidência , Pessoa de Meia-Idade
20.
Genes Chromosomes Cancer ; 28(3): 300-7, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10862036

RESUMO

Constitutive large deletions and duplications of BRCA1 resulting from Alu-mediated recombination account for a significant proportion of disease-causing mutations in breast and/or ovarian cancer families. Using Southern blot analysis and a protein truncation test (PTT), we have identified a 7.1 kb germline deletion in two families with breast and ovarian cancer. This deletion, which includes exons 8 and 9 and leads to a frameshift at the mRNA level, appears to result from homologous recombination between closely related Alu repeats, one in intron 7 and one in intron 9. In addition to the transcript without exons 8 and 9, analysis of RNA by protein truncation test from individuals with the deletion also identified the presence of alternative splicing of exon 10 from the mutant allele, which results in a transcript that lacks exons 8, 9, and 10. Of interest is that the two American families who carry this deletion are of northern European ancestry and share a common haplotype, suggesting that this deletion may represent a founder mutation. Genes Chromosomes Cancer 28:300-307, 2000.


Assuntos
Processamento Alternativo/genética , Elementos Alu/genética , Proteína BRCA1/genética , Neoplasias da Mama/genética , Deleção Cromossômica , Éxons/genética , Neoplasias Ovarianas/genética , Adulto , DNA de Neoplasias/genética , Feminino , Mutação da Fase de Leitura , Haplótipos , Humanos , Pessoa de Meia-Idade , Recombinação Genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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